Ophthalmic compositions

ABSTRACT

Ophthalmic compositions having negligible side effects on the heart can be obtained by using as the active ingredient an adrenergic β receptor agonist having a high selectivity toward adrenergic β 2  receptor. These compositions are usable as preventives or therapeutics for xerophthalmic disorder and keratoconjunctival disorder.

This application is a 371 of PCT/JP00/08623 filed Dec. 6, 2000.

TECHNICAL FIELD

The present invention relates to an ophthalmic composition containing aselective adrenergic β₂ receptor agonist.

BACKGROUND ART

Tear film covers the ocular surface, consisting of the cornea andconjunctiva, to keep it moisturized and protect it from drying. At thesame time, tears function as a transparent optical transmissive liquidthat maintains the corneal surface flat and smooth for the clear viewingof images. Tears also contain a large number of ingredients such asantibodies that prevent infections by viruses, bacteria, etc.Furthermore, tears play a role in washing away foreign substances whichhappen to get into eyes as well as cellular wastes derived from thecornea and conjunctiva. In addition, tears serve as a supply source ofoxygen, moisture and nutrients for the cornea, which is an avasculartissue, and actively contribute to the healing of eye wounds, serving asa source of various biologically active substances at the time ofkeratoconjunctival disorders (corneal and conjunctival injuries) (OcularSurface no Shindan to Chiryou (Diagnosis and Treatment of OcularSurface), 24-30 (1993)).

Methods known in the art for treating hypolacrimia, xerophthalmia, dryeye, keratoconjunctivitis sicca, and such, which are all accompaniedwith the aberrant tear secretion, involve externally supplementingnatural tears in shortage with artificial tears, and prolonging theretention time of artificial tears in the conjunctival sac by combiningthe artificial tears with viscous materials and such. However, since theactual tears contain a variety of biologically active substances asdescribed above which contribute to the homeostasis and functionalrestoration (healing of injuries) of ocular surface, the mere moisturereplenishment with artificial tears and such is insufficient to act assubstitute for the role of natural tears. Therefore, there has been astrong demand for drugs capable of quantitatively as well asqualitatively improving tear secretion (Atarashii Ganka (NewOphthalmology), 14, 1631-1636 (1997)).

Promotion of tear secretion by isoproterenol, a β adrenergic receptoragonist, has been hitherto reported (Invest. Ophthalmol. Vis. Sci., 20,110-116 (1981)). There exist two subtypes, β₁ and β₂, for the βadrenergic receptors, β₁ being distributed mainly in the heart while β₂is predominantly in the smooth and skeletal muscles. Since isoproterenolis a nonselective β adrenergic receptor agonist which strongly acts oneither β₁ or β₂ receptor, it acts on the heart, wherein the β₁adrenergic receptor is abundant, often causing unfavorable side effectson the cardiovascular system, specifically inducing an increase in theheart rate and an enhancement of heart contractile force. Thus,administration of a nonselective β adrenergic receptor agonist as abronchodilator is often accompanied with side effects on thecardiovascular system. In light of its unfavorable side effects,isoproterenol, a tear secretion promoting agent, is difficult to use asa tear secretion improving agent.

Research aiming at reducing side effects and prolonging actions of βadrenergic receptor agonists, focusing on the organ distribution of βadrenergic receptor subtypes, has been ongoing. In recent years, drugshaving a high selectivity to the β₂ adrenergic receptor with a lowcardiac distribution, so-called selective β₂ adrenergic receptoragonists, have been developed among β adrenergic receptor agonists.Since selective β₂ adrenergic receptor agonists directly act on β₂adrenergic receptors in smooth muscles to dilate bronchus and bloodvessels, and also relax uterus, and such, they are applied to thetreatment of bronchial asthma, threatened abortion, etc. Drugs of thistype are inert to cardiovascular systems in therapeutic doses,expressing no action to increase the heart rate and/or to enhance heartcontractile force. However, there has been no report on actions of theseselective β₂ adrenergic receptor agonists concerning the promotion oftear secretion, increase in protein concentration in tears, and thetreatment of keratoconjunctival and xerophthalmic disorders.

DISCLOSURE OF THE INVENTION

It is an object of this invention to provide an ophthalmic compositionwith as low side effects on the heart as possible, more specifically, toprovide a composition whose side effects on the heart are sufficientlysuppressed and which is capable of promoting tear secretion. It isanother object of this invention to provide a composition which is ableto increase protein concentration secreted in tears.

Present inventors proposed that compounds that promote tear secretionand, moreover promote secretion of tear proteins, which function asbiologically active substance in particular, would be useful for thetreatment of xerophthalmic and keratoconjunctival disorders. Further,they have selected the β adrenergic receptor agonist as candidatecompound for drugs having the activity to promote tear secretion. Todevelop drugs to improve tear secretion targeting the β adrenergicreceptor, it is necessary to avoid side effects thereof on the heart. Tosolve these problems, present inventors paid attention to thedistribution of β adrenergic receptor subtypes in the lacrimal gland andheart. That is, more β₁ adrenergic receptors are distributed in theheart, while more β₂ adrenergic receptors in the lacrimal gland. Presentinventors proposed to avoid side effects on the heart by utilizing thedifference in β adrenergic receptor subtypes in both tissues, anddiscovered that agents that improve tear secretion with less side effecton the heart could be provided by utilizing β adrenergic receptoragonists having a high selectivity for the β₂ adrenergic receptor.Furthermore, they confirmed that β₂ adrenergic receptor agonists, inaddition to promoting tear secretion level, acted to increase theprotein concentration in tears, thereby accomplishing this invention.That is, the present invention relates to the following compositions,methods for improving tear secretion using such compounds, and methodsfor suppressing their side effects.

[1] A composition for treating and/or preventing diseases due toxerophthalmic and/or keratoconjunctival disorders, said compositioncomprising a selective β₂ adrenergic receptor agonist as an activeingredient.

[2] A composition for treating and/or preventing at least one diseaseselected from the group consisting of keratoconjunctivitis sicca,lacrimal hyposecretion, xerophthalmia, dry eye, age-relatedxerophthalmia, Stevens-Johnson syndrome, corneal epithelial disorder,corneal epithelial detachment and keratoconjunctival ulcer, saidcomposition comprising a selective β₂ adrenergic receptor agonist as anactive ingredient.

[3] The composition of [1] or [2], wherein the selectivity of theselective β₂ adrenergic receptor agonist to the β₂ adrenergic receptoris not less than ten times the selectivity to the β₂ adrenergic receptorof isoproterenol.

[4] The composition of any one of [1] to [3], wherein said selective β₂adrenergic receptor agonist is one or more compounds selected from thegroup consisting of clenbuterol, fenoterol, procaterol, salbutamol,salmeterol, hexoprenaline, pirbuterol, mabuterol, bambuterol,formoterol, meluadrine, tulobuterol, levosalbutamol, and their salts.

[5] The composition of any one of [1] to [4], wherein said compositionis a pharmaceutical preparation formulated for oral administration.

[6] The composition of any one of [1] to [4], wherein said compositionis a pharmaceutical preparation formulated for parenteraladministration.

[7] The composition of [6], wherein said pharmaceutical preparationformulated for parenteral administration is an eye drop (an ophthalmicsolution) or an eye ointment (ophthalmic ointment).

[8] The composition of [7], wherein said composition comprises 0.00001to 5 w/v % of a selective β₂ adrenergic receptor agonist in the whole ofthe eye drop or eye ointment.

[9] A method for improving tear secretion, said method comprisingadministering a selective β₂ adrenergic receptor agonist.

[10] The method of [9], wherein said improved tear secretion involves anincrease in tear secretion level and/or protein concentration in tears.

[11] A method for reducing the side effects of a tear secretionimproving agent comprising a β adrenergic receptor agonist as an activeingredient, said method in which a compound having a stimulatoryactivity selective to the β₂ adrenergic receptor is used as a βadrenergic receptor agonist.

[12] A composition for improving tear secretion comprising a selectiveβ₂ adrenergic receptor agonist as an active ingredient.

The present invention provides an ophthalmic composition containing aselective β₂ adrenergic receptor agonist as an active ingredient. Inthis invention, an “ophthalmic composition” means a medical compositionwhich is administered solely for the purpose of treating and preventingdisorders of the eye. Therefore, for example, in addition topharmaceutical preparations for local administration, such as eye drops,eye ointment, etc., other types of preparations, administered for thepurpose of treating and preventing disorders of the eye, are alsoincluded in the ophthalmic composition of this invention, even thoughthey are indirectly administered to eyes, as in the case of oralpharmaceutical preparations. β₂ adrenergic receptor agonists used inthis invention are compounds which selectively act on the β₂ adrenergicreceptor, that is, selective β₂ adrenergic receptor agonists.Selectivity means that, even at a drug dose at which negligible sideeffects on the heart are detectable, a stimulatory activity of the drugspecific for the β₂ adrenergic receptor, such as broncodilating activityand/or lung function improving activity, can be observed. Selective β₂adrenergic receptor agonist is highly specific to the β₂ adrenergicreceptor, as indicated by the ratio of stimulating activities thereoffor the β₁ and β₂ adrenergic receptors used as index. From that reason,selective β₂ adrenergic receptor agonists exert no significant sideeffects on the cardiovascular system, such as the increase in the heartrate and heart excitation.

Selectivity of a drug to the β₂ adrenergic receptor can be representedusing as an index the ratio between the pharmacological activity of thedrug directed by the β₁ adrenergic receptor and that directed by the β₂adrenergic receptor. Pharmacological activity directed by the β₁adrenergic receptor is represented by, for example, the concentration ofa drug needed to show an increase in the heart rate (EC50) in an excisedatrium. On the other hand, pharmacological activity directed by the β₂adrenergic receptor is represented by, for example, the concentration ofa drug needed to show a relaxation of smooth muscle (EC50) in an excisedtrachea or uterus. Thus, specificity to the β₂ adrenergic receptor canbe represented by a value obtained by dividing the former EC50 (β₁) bythe latter EC50 (β₂). A larger value indicates a higher specificity of acompound to the β₂ adrenergic receptor. In this invention, a selectiveβ₂ adrenergic receptor agonist means a compound having a higherspecificity to the β₂ adrenergic receptor than the specificity to thereceptor of isoproterenol. Excised organs used for comparingpharmacological activity are generally obtained from guinea pigs.

More preferably, the selective β₂ adrenergic receptor agonist of thepresent invention is a compound having specificity to β₂ adrenergicreceptor which is at least 10 times, preferably 100 times, morepreferably 1000 times higher than that of isoproterenol. Examples ofrelative specificities of selective β₂ adrenergic receptor agonists tothe tracheal smooth muscle are as follows: fenoterol's specificity isabout 20 times higher than that of isoproterenol; salbutamol's is about30 times higher; pirbuterol's is about 260 times higher; formoterol's isabout 630 times higher; procaterol's is about 2000 times higher; andclenbuterol's is about 7000 times higher than that of isoproternol.Herein, isoproterenol as a standard compound for comparison can take theform of a hydrochloride or sulfate.

Alternatively, a selective β₂ adrenergic receptor agonist which bindswith a β₂ adrenergic receptor with affinity not less than 10 times thatwith which it binds with a β₁ adrenergic receptor can be utilized as atear secretion improving agent of this invention in a therapeuticallyeffective dose thereof. Affinity of a selective β₂ adrenergic receptoragonist to a β₂ adrenergic receptor is preferably not less than 100times, more preferably not less than 1000 times that to a β₁ adrenergicreceptor. Binding affinity to a β₁ or β₂ adrenergic receptor can beconfirmed by conventional methods known in the art. For example, theaffinity can be measured by a competitive binding assay using thecardiac muscle tissue to test a β₁ adrenergic receptor, and the lungtissue to test a β₂ adrenergic receptor.

Since the composition of this invention comprises an agonist thatselectively acts on the β₂ adrenergic receptor, it does not act on theheart, an organ with little distribution of the β₂ adrenergic receptor.For that reason, the composition can effectively avoid side effects onthe heart, in spite of the fact that it comprises a β adrenergicreceptor agonist as an active ingredient. As a result, side effectsthereof on the heart are negligible in doses which improving effects ontear secretion can be expected.

Examples of β₂ adrenergic receptor agonists used in this invention areselective β₂ adrenergic receptor agonists or salts thereof such asclenbuterol, fenoterol, procaterol, salbutamol, salmeterol,hexoprenaline, pirbuterol, mabuterol, banbuterol, formoterol,meluadrine, tulobuterol, levosalbutamol, etc. Furthermore, derivativesof these selective β₂ adrenergic receptor agonists and salts thereof maybe used. In this invention, salts are referred to as medicinallyacceptable non-toxic salts. Examples of these salts are hydrochlorides,sulfates, hydrobromides, valerates, citrates, gluconates, succinates,tartarates, fumarates, etc. All of these drugs have selectively highaffinities to the β₂ adrenergic receptor as compared with the β₁adrenergic receptor. Selective β₂ adrenergic receptor agonists areclassified by the structural modification into the short acting type,having a bronchial dilation action duration time of less than 6 h, andthe long acting type, having a bronchial dilation action duration timenot less than 6 h. In this invention, either type can be used. Amongthem, from the aspect of prolonged protection of the corneal surface,the long acting type is more preferable. The long acting type includespirbuterol, fenoterol, procaterol, clenbuterol, mabuterol, salmeterol,formoterol, tulobuterol, etc. In this invention, selective β₂ adrenergicreceptor agonists can be used singly or in combination, i.e. a pluralityof these compounds.

A variety of proteins such as IgG, IgA, EGF, lactoferrin, FGF, lysozyme,fibronectin, etc. are secreted into tears. All of these selective β₂adrenergic receptor agonists have the action to promote tear secretion.These selective β₂ adrenergic receptor agonists are physiologically aswell as pharmacologically acceptable compounds that act as a promoterfor the secretion of tear proteins. Therefore, with the combination ofthese compounds, the promoting effects on tear secretion and theelevated secretion of a variety of proteins, which have repairingfunctions on keratoconjunctival tissues, etc., can be expected.Specifically, with the combination of these compounds, the improvedfunction to prevent infection accompanied with an increase in IgG andIgA secretion, to stimulate repair of keratoconjunctival tissues andpromote proliferation of corneal epithelial cells and differentiation ofcorneal epithelium, accompanied with the increase in the secretion ofbiologically active substances such as EGF, lactoferrin, FGF, lysozyme,etc., can be expected. Therefore, these compounds can be used for thetreatment and/or prevention of disorders accompanied withkeratoconjunctival injuries.

By this invention, an ophthalmic composition or tear secretion improvingagent comprising a selective β₂ adrenergic receptor agonist as an activeingredient is provided. The composition according to this invention hasthe activity to enhance the secretion level of tears and/or promote thesecretion of proteins into tears. In a preferred embodiment, thecomposition of this invention has the action to promote not only tearsecretion level but also protein secretion into tears.

The composition of this invention can be used as a tear secretionimproving agent based on its tear secretion improving action. In thisinvention, a tear secretion improving agent means a pharmaceuticalpreparation with improving effects on the decrease in the tear secretionlevel and qualitative aberration of tears. Alternatively, a tearsecretion improving agent of this invention can be referred to as apharmaceutical preparation with at least either one of the effects: topromote tear secretion level and protein secretion into tears.

The tear secretion improving agent according to this invention iseffective in improving conditions resulting from a decrease in tearsecretion and qualitative aberration of tears. Decrease in tearsecretion and qualitative aberration of tears are accompanied withsubjective symptoms such as dry sensation (dry eye), foreign substancesensation, burning sensation, congestion, ophthalmalgia, eyestrain,asthenopia, itching eye, uncomfortable feeling of eyes, difficulty toopen eyes. Therefore, the tear secretion improving agent of thisinvention is effective in improving these uncomfortable symptoms.

Alternatively, the composition of this invention can be utilized for thepurpose of, for example, treating and/or preventing the followingsymptoms:

xerophthalmic disorder,

keratoconjunctival disorder,

keratoconjunctivitis sicca,

lacrimal hyposecretion,

xerophthalmia,

dry eye,

age-related xerophthalmia,

Stevens-Johnson syndrome,

corneal epithelial disorder,

corneal epithelial detachment and

keratoconjunctival ulcer.

Furthermore, this invention relates to the use of selective β₂adrenergic receptor agonists in the preparation of ophthalmiccompositions. This invention also relates to the use of selective β₂adrenergic receptor agonists in the treatment and/or prevention ofaforementioned ophthalmic disorders. Alternatively, this inventionrelates to the use of selective β₂ adrenergic receptor agonists in thepreparation of compositions for the treatment and/or prevention ofaforementioned ophthalmic disorders.

Xerophthalmic disorders encompass disorders associated with a decreasein tear secretion level and qualitative aberration in tears can bedetected by tear tests known in the art, such as Schirmer's test, cottonthread test, tear film break-up time (BUT), clearance test andlactoferrin measuring test. Examples of diseases accompanied byxerophthalmic disorders include keratoconjunctivitis sicca, such askeratitis superficialis diffusa, superficial punctate keratitis,keratitis filamentosa, etc., lacrimal hyposecretion, xerophthalmia, dryeye, age-related xerophthalmia and Stevens-Johnson syndrome, etc.Improvement of tear secretion can lead to the treatment and/orprevention of these xerophthalmic disorders.

On the other hand, keratoconjunctival disorders encompass disordersassociated with injuries that can be detected on the corneal epitheliumand/or keratoconjunctiva by fluorescein or rose bengal stains. Examplesof diseases accompanied with keratoconjunctival disorders includecorneal epithelial disorder, corneal epithelial detachment,keratoconjunctival ulcer, etc. Patients with xerophthalmic disordersoften complain of the aforementioned subjective symptoms, but are notalways accompanied with keratoconjunctival injuries. However, progressin xerophthalmic disorders often results in complications due tokeratoconjunctival disorders. The composition of this invention in itspreferred embodiment is effective in treating and/or preventingkeratoconjunctival disorders because the composition has an improvingaction on the concentration of proteins secreted into tears as well asan improving action on tear secretion level. The discovery thatstimulation of the β₂ adrenergic receptor can induce the elevation ofprotein concentration in tears is a novel aspect of this invention.

In addition, this invention is also useful for wearing a contact lens inthe eye. In a state of having a contact lens in, tears opticallyfunction as a tear lens. From the physiological point of view, tearsplay the role of oxygen supplier to the cornea, which is blocked fromthe atmosphere by the contact lens. Furthermore, to contact lens users,the function of tears as a buffering material, to relieve theincongruous feeling associated with the lens, is also important. With atear secretion improving agent according to this invention, contact lenswearers can expect an improvement in their contact lens wearing feeling,eyesight correction and such, by promoting tear secretion.

The ophthalmic composition of this invention can be formulated by knownmethods in the art into eye drops (ophthalmic solutions), injections,eye ointments (ophthalmic ointments), ointments, tablets, capsules,powders, granules, etc., for oral and parenteral administration. Eyedrops or eye ointments, which are parenteral preparations, can be notonly easily administered but also expected to effect rapidly. With theoral pharmaceutical preparation, a duration of efficacy can be expected.

Alternatively, the composition of this invention can be adsorbed on thesurface of contact lens and/or absorbed thereto by soaking. Contact lensconstructing such a dosage form can be a lens aiming at correcting theeyesight, or a transparent film serving as a drug carrier. In the lattercase, the film can be a soluble one. In such an embodiment, theaforementioned contact lens may be brought into contact with the ocularsurface with the hope for the lasting improvement of tear secretion.

The content of a selective β₂ adrenergic receptor agonist as an activeingredient in each pharmaceutical preparation comprising the compositionof this invention can be appropriately altered, corresponding to themethod of its administration, etc. For example, eye drops usuallycontain 0.00001 to 5 w/v %, preferably 0.0001 to 1 w/v % of activeingredient. The pH of eye drops may be in the range acceptable for thegeneral ophthalmic pharmaceutical preparation, specifically adjusted tothe range which is favorable for the stability of the active ingredientand less irritating to the ocular-mucous membrane, for example, a pHrange of 3 to 9, preferably 5 to 8.5, more preferably 5.5 to 7.5. Inaddition, the osmotic pressure of eye drops according to this inventionis preferred to be less irritating to the ocular-mucous membrane.Specifically, the examples of preferred osmotic pressure are usuallyabout 150 to 450 mOsm, preferably about 260 to 360 mOsm. Alternatively,in terms of the osmotic pressure ratio relative to the physiologicalsaline, it is usually about 0.6 to 2.0, preferably about 0.7 to 1.7,more preferably about 0.8 to 1.5.

The composition of this invention includes eye drops comprising aselective β₂ adrenergic receptor agonist and buffering agent. Eye dropsaccording to this invention may further contain an isotonizing agent,and may be supplemented with a viscosifying agent and a humectant toretain tears on the ocular surface to keep it moist. Also, to augmentthe wetness of ocular surface, eye drops may be supplemented with asurfactant and a wetting agent, such as an essential oil or componentsthereof, etc. Eye drops of this invention can be further formulated intopharmaceutical preparations, as the occasion demands, utilizing avariety of commonly used supplements such as preservatives, stabilizers,antioxidants, pH adjusters, chelating agents, absorption enhancers, etc.which are readily combinable with conventional eye drops.

Buffering agents can be any compounds, provided they can adjust eyedrops to the physiological pH; however, they are preferably compoundswhich exhibit no side effects on the live body at their doses. Examplesof buffering agents include borate buffers, citrate buffers, phosphatebuffers, tartarate buffers, acetate buffers, carbonate buffers, andamino acid salts, etc.

Isotonizing agents comprise carbohydrates, salts, etc. that are requiredto give the physiological osmotic pressure to eye drops. Examples ofisotonizing agents include carbohydrates such as sorbitol, mannitol,glucose, etc., polyalcohols such as glycerine, propylene glycol,polyethylene glycol, etc., and salts such as sodium chloride, potassiumchloride, etc.

Examples of preservatives include quaternary ammonium salts, such asbenzalkonium chloride, benzethonium chloride, etc., p-hydroxybenzoicacid esters, such as methyl p-hydroxybenzoate, etc., sorbic acid andsalts thereof, chlorobutanol, chlorhexidine gluconate,alkylpolyamino-ethylglycine, etc.

Examples of viscosifying agents include hydroxyethylcellulose,hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone,polyvinyl alcohol, hyaluronic acid and salts thereof, etc.

As humectant, for example, carbohydrates and polyalcohols can be used.Examples of carbohydrates are mannitol, dextran, alginic acid (and saltsthereof), chondroitin sulfate (and salts thereof), or hyaluronic acid(and salts thereof), etc. Examples of polyalcohols are glycerin,polyethylene glycol or propylene glycol, etc.

A variety of surfactants, which are classified into non-ionic, cationic,anionic and amphoteric surfactants and such, can be utilized. Examplesof nonionic surfactants include, for example,polyoxyethylenepolyoxypropylene block copolymer, polysorbate,polyoxyethylenesorbitan esters of fatty acids, polyoxyethylenehydrogenated castor oil, etc. Examples of cationic surfactants arePOE-POP block-substituted alkylenediamine comprised of alkylenediamines(ethylenediamine, etc.) added with the polyoxyethylene(POE)-polyoxypropylene (POP) block. Anionic surfactants includealkylbenzensulfonic acid and alkylsulfates. In addition, examples ofamphoteric surfactants are alkylpolyaminoethylglycine hydrochloride,etc.

As essential oil, peppermint oil, fennel oil, rose oil, bergamot oil,etc. can be used. Examples of essential oil components are menthol,camphor, borneol, etc.

Surfactants, such as polysorbate 80, polyoxyethylene hydrogenated castoroil, etc., water-soluble polymers such as cyclodextrins, polyvinylpyrrolidone, methylcellulose sodium, hydroxypropylmethylcellulose,methylcellulose, and ethanol, etc., can be used as stabilizers (orsolubilizers). Examples of antioxidants are ascorbic acid, sodiumascorbate, tocopherol, sodium thiosulfate, sodium hydrogen sulfite, etc.Examples of chelating agents are sodium edetate (disodiumethylenediamine tetraacetate) sodium citrate, etc. Examples of pHadjusters are hydrochloric acid, citric acid, phosphoric acid, aceticacid, tartaric acid, sodium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydrogen carbonate, boric acid, sodium borate, etc.

The composition of this invention includes oral drugs, comprising aselective adrenergic β₂ receptor agonist, excipient and lubricant. Oraldrugs usually contain 0.3 μg to 300 mg, preferably 30 μg to 150 mg of aselective adrenergic β₂ receptor agonist per 1 g of pharmaceuticalpreparation. Oral drugs can be prepared according to methods that arestandard in the art. That is, oral drugs of this invention can beformulated into pharmaceutical preparations by combining a variety ofcommonly used adjuvants, such as excipients, lubricants, disintegrators,binders, and others, including sweetening agents, flavoring agents,corrigents, adsorbents, preservatives, humectants, antistatic agents,etc. as the occasion demands. Examples of excipients include cornstarch, potato starch, sucrose, talc, kaolin, calcium sulfate, calciumcarbonate or crystalline cellulose, etc. Examples of lubricants aremagnesium stearate, calcium stearate, etc.

As disintegrator, calcium carboxymethylcellulose, low substitutedhydroxymethylcellulose, etc. can be used. As binder,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, gelatin, cellulose polymers, acrylic acidpolymers, methylcellulose, arabic gum, polyvinyl alcohol, etc. can beused.

Doses of the composition of this invention are appropriately selecteddepending on symptoms, ages, dosage forms, etc. In the case of eyedrops, with the instillation of 0.00001 to 5 w/v % eye drops once toseveral times a day, treatment or preventive effects can be expected. Onthe other hand, in the case of oral drugs, usual doses of 10 μg to 100mg a day may be administered once or divided into several portions.

BEST MODE FOR CARRYING OUT THE INVENTION TEST EXAMPLE 1

Using Japanese albino strain male rabbits, eye drops containingadrenergic β receptor agonists were examined for their tear secretionpromoting actions.

1. Preparation of Test Solutions

Prior to use, each adrenergic β receptor agonist was dissolved in aphosphate buffer solution to prepare a 0.1 w/v % solution, which wasadjusted to the pH ranging 6.0 to 7.5. Compounds used in this experimentare shown below. The phosphate buffer solution served as control.

Selective Adrenergic β₁ Receptor Agonist:

dobutamine hydrochloride (Funakoshi)

Selective Adrenergic β₂ Receptor Agonists:

clenbuterol hydrochloride (Sigma),

fenoterol hydrobromide (Sigma), and

procaterol hydrochloride (Sigma)

2. Experimental Method

Six rabbits (12 weeks old, weighing 2.0 to 2.5 kg) were used in eachgroup. A test solution (50 μl) was instilled into one eye of the rabbit,and amounts of tears secreted were measured for 5 minutes from 15 to 10min prior to the instillation of the test solution, for 5 minutes from 5to 10 min and for 5 minutes from 20 to 25 min after the instillation,three times in total, by the following method. A local anesthetic, 0.4w/v % oxybuprocaine hydrochloride solution (Santen Pharmaceutical) (50μl) was instilled into one eye of the rabbit, 5 min later the remainingeye drops and tears were once soaked up using a water absorbing paper,and then a previously weighed filter paper (5×35 mm) was inserted in thelower eyelid area. Five minutes later, the filter paper was recovered,weighed and the increment in weight was taken as the amount of secretedtears. With the amount of secreted tears prior to the instillation of atest solution taken as a basal secretion amount, ratios of increases inthe amount of secreted tears to the basal secretion amount were used asthe rate of increase in the tear secretion (%).

3. Results

As shown in Table 1, though there were some differences among drugs, therate of increase in the tear secretion was improved by the instillationof all the selective adrenergic β₂ receptor agonists tested as comparedwith that prior to the instillation. On the other hand, the rate ofincrease in the tear secretion by dobutamine, a selective adrenergic β₁receptor agonist, was 8% for 5 minutes from 5 to 10 min after theinstillation, and −29% for 5 minutes from 20 to 25 min after that ascompared with the basal secretion amount prior to the instillation,showing almost no improvement. With the phosphate buffer solution,almost no improvement was also observed in the rate of increase in thetear secretion. That is, selective adrenergic β₂ receptor agonists wereshown to have an excellent activity to promote tear secretion.

TABLE 1 Rate of increase in tear secretion (*) Drug For 5 minutes For 5minutes concentration from 5 to 10 min from 20 to 25 min (w/v %) afterinstillation after instillation Dobutamine 0.1 8 −29 Clenbuterol 0.1 3629 hydrochloride Fenoterol 0.1 144 49 hydrobromide Procaterol 0.1 118 43hydrochloride Phosphate buffer — 9 5 solution * %: ratio of increase inthe tear secretion as compared with the basal secretion amount.

Test Example 2

Using Japanese albino strain male rabbits, eye drops containingadrenergic β receptor agonists were examined for their actions topromote the tear protein secretion.

1. Preparation of Test Solutions

Prior to use, each adrenergic β receptor agonist was dissolved in aphosphate buffer solution to prepare 0.1 w/v % solution, and adjusted tothe pH ranging 6.0 to 7.5. Compounds and compositions of eye drops usedin this experiment are shown below using the phosphate buffer solutionas control.

Selective Adrenergic β₁ Receptor Agonist:

dobutamine hydrochloride (Funakoshi)

Selective Adrenergic β₂ Receptor Agonists:

clenbuterol hydrochloride (Sigma),

fenoterol hydrobromide (Sigma), and

procaterol hydrochloride (Sigma)

2. Experimental Method

Six rabbits (12 weeks old, weighing 2.0 to 2.5 kg) were used in eachgroup. A test solution (50 μl) was instilled into one eye of the rabbit,and protein concentrations in tears were measured for 5 minutes from 15to 10 min prior to the instillation of the test solution, for 5 minutesfrom 5 to 10 min and for 5 minutes from 20 to 25 min after theinstillation, three times in total, using the following method. A localanesthetic, 0.4 w/v % oxybuprocaine hydrochloride solution (SantenPharmaceutical) (50 μl) was instilled into one eye of the rabbit, 5 minlater the remaining eye drops and tears were once soaked up using awater absorbing paper, and then a previously weighed filter paper (5×35mm) was inserted in the lower eyelid area. Five minutes later, thefilter paper was recovered, weighed and the increment in weight wastaken as the amount of secreted tears. Immediately after measuring theamount of secreted tears, the filter paper thus recovered was placed ina 1.5-ml test tube, 1 ml of the phosphate buffer solution (pH 7.4) wasadded thereto, and the test tube was stirred for 30 s. After the removalof the filter paper followed by the centrifugation of the solution at3,000 rpm for 5 min, a stain reagent of Bio-Rad protein assay kit wasadded to the supernatant to measure the amount of protein and calculatethe total amount of protein in the filter paper. From the total amountof protein and that of secreted tears, the protein concentration intears was calculated.

With the protein concentration in tears prior to the instillation of atest solution taken as a basal protein concentration, ratios ofincreases in respective protein concentrations relative to the basalprotein concentration were used as the rate of increase in proteinconcentration in tears (%)

3. Results

As shown in Table 2, the rate of increase in protein concentration oftears by 0.1 w/v % procaterol was 76% for 5 minutes from 5 to 10 minafter its instillation, and 109% for 5 minutes from 20 to 25 min afterthat, as compared with the basal secretion amount prior to theinstillation, demonstrating the increase in protein concentration intears. The rates of increase in protein concentration in tears by 0.1w/v % clenbuterol and 0.1 w/v % fenoterol were both 16% for 5 minutesfrom 5 to 10 min after their instillations, but elevated to 53% and 43%,respectively, for 5 minutes from 20 to 25 min after the instillationsover the basal rate prior to the instillations, showing the increase inprotein concentrations. On the other hand, the rate of increase inprotein concentration of tears by 0.1 w/v % dobutamine was 9% 5 to 10min after its instillation, and −19% for 5 minutes from 20 to 25 minafter that as compared with the basal protein concentration prior to theinstillation with almost no change observed. That is, selectiveadrenergic β₂ receptor agonists were confirmed to have an excellentaction to promote the protein secretion in tears.

TABLE 2 Rate of increase in tear protein concentration (*) Drug For 5minutes For 5 minutes concentration from 5 to 10 min from 20 to 25 min(w/v %) after instillation after instillation Dobutamine 0.1 9 −19Clenbuterol 0.1 16 53 hydrochloride Fenoterol 0.1 16 43 hydrobromideProcaterol 0.1 76 109 hydrochloride Phosphate buffer — −3 4 solution *%:ratio of increase of protein concentration in tears relative to thebasal concentration.

Test Example 3 Effects of Systemic Administration

Using Japanese albino strain male rabbits, injections containingselective adrenergic β₂ receptor agonists were examined for theiractions to promote the tear secretion and the protein secretion intears.

1. Method for Preparing Test Solutions

Prior to use, clenbuterol hydrochloride was dissolved in a physiologicalsaline (concentration 50 μg/ml), and adjusted to the pH in the range 6.0to 7.5. The physiological saline was used as control.

2. Experimental Method

Six rabbits (11 to 12 weeks old, weighing 2.4 to 2.6 kg) were used ineach group. The test solution (50 μg/rabbit) was administered into theear vein, and amounts of tears secreted were measured 15 to 10 min priorto the administration of the test solution, 5 to 10 min, 20 to 25 min,40 to 45 min, 60 to 65 min and 120 to 125 min after the administration,six times in total, by the following method. A local anesthetic, 0.4 w/v% oxybuprocaine hydrochloride solution (Santen Pharmaceutical) (50 μl)was instilled into one eye of a rabbit, 5 min later the remaining eyedrops and tears were once soaked up using a water absorbing paper, andthen a previously weighed filter paper (5×35 mm) was inserted in thelower eyelid area. Five minutes later, the filter paper was recovered,weighed and the increment in weight was taken as the amount of secretedtears. After measuring the amount of secreted tears, the filter paperthus recovered was placed in a 1.5-ml test tube, 1 ml of the phosphatebuffer solution (pH 7.4) was added thereto, and the test tube wasvortexed for 30 s. After the removal of the filter paper, followed bythe centrifugation at 3,000 rpm for 5 min, a stain reagent of Bio-Radprotein assay kit was added to the supernatant to measure the amount ofprotein and calculate a total amount of protein in the filter paper.From the total amount of protein and that of secreted tears, the proteinconcentration in tears was calculated. With the amount of secreted tearsprior to the administration of a test solution taken as the basalsecretion amount, ratios of increases in the secreted tears to the basalsecretion amount were used as the rate of increase in the tear secretion(%). In addition, with the protein concentration in tears prior to theadministration of a test solution taken as the basal proteinconcentration, ratios of increases in respective protein concentrationsrelative to the basal protein concentration were used as the rate ofincrease in protein concentration in tears (%).

3. Results

As shown in Table 3, by the intravenous administration of clenbuterol,significant increases in the amount of tear secretion as well as theprotein concentration in tears were observed. That is, effects ofselective adrenergic β₂ receptor agonist on the improvement of tearsecretion were observed also by the systemic administration thereof.These results have suggested that similar effects can be obtained alsoby the oral administration of the drug.

TABLE 3 Time after administration (min) 5-10 20-25 40-45 60-65 120-125Clenbuterol Rate of increase in tear 155 146 133 68 58 hydrochloridesecretion (%) Rate of increase in protein 139 148 179 188 171concentration in tears (%) Physiological Rate of increase in tear 6 18−2 11 −4 saline secretion (%) Rate of increase in protein −3 14 7 20 18concentration in tears (%)

From the results of test examples 1 to 3, it has been demonstrated thatthe tear secretion improving agent of this invention has the activitiesto promote the tear secretion level and to enhance the proteinconcentration secreted in tears, and that it is useful as a preventiveor therapeutic for diseases caused by xerophthalmic and/orkeratoconjunctival disorders, with negligible side effects on the heartdue to its low pharmacological activities to adrenergic β₁ receptors.

EXAMPLE 1

Tablets for oral administration were prepared which contained pirbuterolhydrochloride as a selective adrenergic β₂ receptor agonist.

Corn starch (290 g), crystalline cellulose (500 g), calciumcarboxy-methylcellulose (210 g) and pirbuterol hydrochloride (50 g) weremixed, granulated, dried, and pulverized to powders by the standardmethod. To these powders, an appropriate amount of magnesium stearatewas further added and mixed to obtain a powder mixture for compressing,which was compressed to prepare tablets (containing 10 mg/tabletpirbuterol hydrochloride). These tablets are to be administered 1 to 6tablets/day for a male adult weighing 50 kg.

EXAMPLE 2

Eye drops were prepared which contained fenoterol hydrobromide as aselective adrenergic β₂ receptor agonist.

Composition of eye drops (in 100 ml):

fenoterol hydrobromide 100 mg sodium chloride 0.500 g potassium chloride0.080 g sodium dihydrogen phosphate 0.150 g disodium hydrogen phosphate0.100 g sodium edetate 0.005 g 0.1 N sodium hydroxide solutionappropriate amount sterilized pure water appropriate amount total volume100 ml

Sodium edetate was slowly dissolved in about 80 ml of water. To thissolution of sodium edetate were added sodium dihydrogen phosphate anddisodium hydrogen phosphate, and dissolved. Next, to this solution,sodium chloride and potassium chloride were added and dissolved. To theresulting solution, fenoterol hydrobromide was added and the solutionwas adjusted to about pH 6.0 to 7.5 with 0.1 N sodium hydroxidesolution, and made to a total volume 100 ml. Eye drops thus preparedwere filtered using an 0.2 μm pore cellulose acetate filter, and filledup into a sterilized plastic container. Eye drops are instilled 1 to 3drops every time and 3 to 6 times a day.

EXAMPLE 3

Eye drops were prepared which contained salbutamol sulfate as aselective adrenergic β₂ receptor agonist.

Composition of eye drops (in 100 ml):

salbutamol sulfate 100 mg sodium chloride 0.500 g potassium chloride0.080 g sodium dihydrogen phosphate 0.150 g disodium hydrogen phosphate0.100 g sodium edetate 0.005 g 0.1 N sodium hydroxide solutionappropriate amount sterilized pure water appropriate amount total volume100 ml

Eye drops are prepared in a similar manner as described in Example 2,and instilled 1 to 3 drops every time and 3 to 6 times a day.

EXAMPLE 4

Eye drops were prepared which contained procaterol hydrochloride as aselective adrenergic β₂ receptor agonist.

Composition of eye drops (in 100 ml):

procaterol hydrochloride 10 mg sodium chloride 0.700 g potassiumchloride 0.100 g boric acid 1.000 g sodium borate 0.200 g sodium edetate0.050 g 0.1 N sodium hydroxide solution appropriate amount sterilizedpure water appropriate amount total volume 100 ml

Sodium edetate was slowly dissolved in about 80 ml of water. To thissolution of sodium edetate were added boric acid and sodium borate, anddissolved. Next, to this solution, sodium chloride and potassiumchloride were added and dissolved. To the resulting solution was thenadded procaterol hydrochloride, and the solution was adjusted to aboutpH 6.0 to 7.5 with 0.1 N sodium hydroxide solution, and made to a totalvolume 100 ml. Eye drops thus prepared were filtered using an 0.2 μmpore cellulose acetate filter, and filled up into a sterilized plasticcontainer. Eye drops are instilled 1 to 3 drops every time and 3 to 6times a day.

EXAMPLE 5

Eye drops were prepared which contained pirbuterol hydrochloride as aselective adrenergic β₂ receptor agonist.

Composition of eye drops (in 100 ml):

pirbuterol hydrochloride 10 mg sodium chloride 0.700 g potassiumchloride 0.100 g boric acid 1.000 g sodium borate 0.200 g sodium edetate0.050 g 0.1 N sodium hydroxide solution appropriate amount sterilizedpure water appropriate amount total volume 100 ml

Eye drops are prepared in a similar manner as described in Example 4,and instilled 1 to 3 drops every time and 3 to 6 times a day.

EXAMPLE 6

Eye drops were prepared which contained clenbuterol hydrochloride as aselective adrenergic β₂ receptor agonist.

Composition of eye drops (in 100 ml):

clenbuterol hydrochloride 1 mg sodium chloride 0.500 g potassiumchloride 0.080 g sodium dihydrogen phosphate 0.150 g disodium hydrogenphosphate 0.100 g sodium edetate 0.005 g 0.1 N sodium hydroxide solutionappropriate amount sterilized pure water appropriate amount total volume100 ml

Eye drops are prepared in a similar manner as described in Example 2,and instilled 1 to 3 drops every time and 3 to 6 times a day.

Industrial Applicability

By the present invention, an ophthalmic composition with negligible sideeffects on the heart has been provided. The composition of thisinvention is excellent in promoting not only tear secretion level butalso protein secretion into tears. Since the proteins in tears compriseingredients participating in the maintenance and repair of cornealfunctions, the composition of this invention is useful for the treatmentand prevention of a variety of ophthalmic disorders.

The composition of this invention can be applied to, for example,preventives or therapeutics for diseases associated with xerophthalmicand keratoconjunctival disorders.

What is claimed is:
 1. A method for improving tear secretion, saidmethod comprising administering to a subject in need of an improvementin tear secretion one or more compounds selected from the groupconsisting of (a) clenbuterol, (b) fenoterol, (c) salbutamol, (d)salmeterol, (e) hexoprenaline, (f) pirbuterol, (g) mabuterol, (h)bambuterol, (i) formoterol, (j) meluadrine, (k) tulobuterol, (l)levosalbutamol, and (m) salts of (a)-(l).
 2. The method of claim 1,wherein said improvement in tear secretion comprises an increased tearsecretion level or an increased protein concentration in tears.
 3. Themethod of claim 1, wherein the administration is parenteral.
 4. Themethod of claim 3, wherein the administration is by instillation in theeye.
 5. The method of claim 1, wherein the administration is oral.